Cardiovascular disease and its associated maladies, dysfunctions and complications are a principal cause of disability and the chief cause of death. One specific factor significantly contributing to this pathophysiologic process is atherosclerosis, which has been generally recognized as the leading health care problem both with respect to mortality and health care costs.
Atherosclerosis is characterized by the deposition of fatty substances, primarily cholesterol, resulting in plaque formation on the inner surface of the arterial wall and degenerative change to the arteries.
It is now well established that cardiovascular disorders including myocardial infarction, coronary heart disease, hypertension and hypotension, cerebrovascular disorders including stroke, cerebral thrombosis and memory loss due to stroke; peripheral vascular disease and intestinal infarction are caused by blockage of arteries and arterioles by atherosclerotic plaque. Atherosclerotic plaque formation is multi-factorial in its production. Numerous studies have demonstrated that a low plasma concentration of high-density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis. HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol; cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL), intermediate density lipoprotein (IDL), and very low density lipoprotein (VLDL). Since low levels of HDL cholesterol increase the risk of atherosclerosis, method for elevating plasma HDL cholesterol would be beneficial for the treatment of atherosclerosis and other diseases associated with the accumulation of lipid in the blood vessels.
Combination therapies for the treatment of diseases, which are affected by low levels of HDL-cholesterol and/or high levels of LDL-cholesterol and triglycerides, for example, atherosclerosis and cardiovascular diseases, have been described in the literature. For example, U.S. Pat. No. 6,586,448 discloses pharmaceutical combination compositions comprising CETP inhibitor and other therapeutic agents, for example, HMG-COA reductase inhibitor, a PPAR agonist or fibrate, for the treatment of diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides. U.S. Pat. No. 6,462,091 discloses combinations of CETP inhibitor and HMG-COA reductase inhibitor for cardiovascular indications. Combinations of CETP inhibitor and HMG-COA reductase inhibitor have also been disclosed in PCT publication Nos. WO 04/004778, WO 04/056359 or WO 04/098583; U.S. Patent application Nos. 20040053842 or 20040132771. U.S. Pat. No. 6,534,088 discloses combinations of HMG-COA reductase inhibitor and fibrate for treatment of patients with dyslipidemia, hyperlipidemia, hypercholesterolemia and related conditions. Combinations of fibrate and HMG-COA reductase inhibitor have also been disclosed in U.S. Pat. No. 6,511,985; PCT Publication Nos. WO 2005/034908, WO 03/013607, WO 01/37831. U.S. Pat. No. 6,420,417 discloses combinations of ileal bile acid transport inhibiting benzothiepines and HMG-COA reductase inhibitors for treating hyperlipidemic conditions. Combinations of ileal bile acid transport inhibitor and HMG-COA reductase inhibitor have also been disclosed in U.S. Pat. Nos. 6,642,268 and 6,268,392. PCT Publication No. WO 03/080070 discloses combinations of HMG-COA reductase inhibitor and insulin secretion enhancer or insulin sensitizer. Other references describing such combinations are European Patent Application No. 0753298, 1510208, 1523316; PCT Publication No. WO 2005/018626. PCT Publication No. WO 03/088962 discloses combination therapy using a PPAR agonist and other therapeutic agents, for example, HMG-COA reductase inhibitor, a bile acid sequestrant or CETP inhibitor. Other references disclosing such combinations are PCT Publication No. 03/013608; U.S. Patent application No. 2005/0032878. PCT Publication No. WO 04/004777 discloses CETP inhibitors and antihypertensive agents as well as optionally HMG-COA reductase inhibitors.
Inflammatory diseases are all characterized by the presence of mediators that recruit and activate different inflammatory cells which release enzymes or oxygen radicals causing symptoms, the persistence of inflammation and when chronic, destruction or disruption of normal tissue.
Combination therapies for the treatment of inflammatory diseases have been described in the literature. For example, U.S. Patent Publication No. 2002/0052312A1 discloses combination therapy of chronic obstructive pulmonary disease using muscarinic receptor antagonists in combination with beta.2-agonist, antitussive, corticosteroid, decongestant, histamine H1 antagonist (antihistamine), dopamine antagonist, leukotriene antagonist, 5-lipooxygenase inhibitor, phosphodiesterase IV inhibitor, VLA-4 antagonist, and theophylline. PCT Publication No. WO 2005/009340 describes methods for the treatment or prevention of respiratory disorders with a cycloxygenase-2 inhibitor in combination with a muscarinic receptor antagonist and compositions thereof. U.S. Publication No. 2005/0063911 discloses combined doses of Formoterol and an anticholinergic agent. PCT Publication No. WO 04/019985 discloses pharmaceutical products and compositions comprising specific anticholinergic agents, beta-2 agonists and corticosteriods. PCT Publication No. WO 02/096422 discloses combinations of a dopamine D2-receptor agonist and tiotropium or a derivative thereof for treating obstructive airways and other inflammatory diseases. PCT Publication No. WO 03/066063 discloses pharmaceutical compositions comprising 17alpha-furanylesters of 17beta-carbothiate androstanes with a muscarinic receptor antagonists. U.S. Publication No. 2004/0097555 discloses pharmaceutical agents comprising one or more kinds of a p38 MAP kinase inhibitor and/or a TNF-alpha production inhibitor and one or more kinds of drugs selected from (1) a non-steroidal anti-inflammatory drug, (2) a disease-modifying anti-rheumatic drug, (3) an-anti-cytokine drug, (4) an immunomodulator, (5) a steroid and (6) a c-Jun N-terminal kinase inhibitor in combination, which has been said to be useful as a prophylactic or therapeutic agent of the diseases rheumatism, arthritis and other diseases. PCT Publication No. WO 95/28926 discloses a pharmaceutical composition for treating multiple sclerosis comprising an effective amount of a combination of a PDE IV inhibitor and an anti-inflammatory or immunomodulatory drug in a pharmaceutically acceptable carrier. PCT Publication No. WO 01/13953 and U.S. Publication No. 20040034087 disclose the combined administration of PDE inhibitors and beta 2 adrenoceptor agonists for the treatment of respiratory tract disorders. PCT Publication No. WO 01/32127 discloses the treatment of pulmonary diseases such as chronic obstructive pulmonary disease or asthma by administering a phosphodiesterase 4 inhibitor in combination with anti-inflammatory corticosteroid. PCT Publication No. WO 2004/067006 discloses treatments and methods for PDE IV-related conditions and for TNF-alpha-related conditions using a combination of a PDE IV inhibitor and a TNF-alpha antagonist. PCT Publication No. WO 2005/041864 discloses a method for the prevention and/or treatment of respiratory inflammation, and in particular asthma and COPD, in a subject in need of such prevention or treatment, the method comprising administering to the subject a cycloogenase-2 inhibitor in combination with a phosphodiesterase 4 inhibitor.
Despite the existence of such combinations for the treatment or prophylaxis of cardiovascular diseases or inflammatory diseases, there remains a need for safe and effective combination products or medicaments for the treatment or prophylaxis of cardiovascular diseases or inflammatory diseases.